Molecular recognition of ingested nutrients results in the secretion of gastrointestinal hormones regulating digestion and gut motility necessary for absorption of these nutrients. Amino acids, short chain fatty acids, carbohydrates and changes in intraluminal pH are known potent stimulators of gastrin, cholecystokinin and secretin, some of the most important gastrointestinal hormones regulating digestion, secretion and motility. The cells responsible for chemosensation of these nutrients are presumed to be scattered along the mucosal layer lining the gastrointestinal tract and may possibly be neurons within the enteric nervous system. The inherent dispersed nature of these chemosensory cells and the lack of any known markers for their identification create a difficult problem for solving the molecular basis of nutrient recognition. Calcium acting at the calcium sensing receptor on gastric G cells has been shown to stimulate the secretion of gastrin. The CaSR has been shown to be a multimodal sensor for amino aicds and pH in addition to divalent cations. Therefore, we hypothesised that the gastric calcium sensing receptor (CaSR) expressed on antral G cells is the physiologically relevant sensor mediating peptone, amino acids (especially aromatic amino acids) and pH stimulated gastrin release in vivo. This work utilized CaSR and parathyroid hormone (PTH) gene deleted mice provided by Martin R. Pollak (JCI 111:1021-1028, 2003). Plasma gastrin response to peptone, phenylalanine (Phe) and pH was assessed in littermates homozygous deleted (KO) (CaSR- /- /PTH- / -), heterozygous (HET) (CaSR+ /- /PTH- / -) and wild type (WT) (CaSR+ /+/PTH- / -) for the CaSR gene or WT C57/B6 mice. Mice were fasted overnight and either fed ad libitum or gavaged with either peptone (8%), Phe (100 mM), or Hepes (150 mM, pH 7.0) as a bolus or parenteral carbacol (5 mg) or bombesin (50 ug/kg) and the peak gastrin response for each agent was measured by RIA. Gastric acid secretion were measured in response to gastrin -17 (1 mg/kg), histamine (10 mg/kg) or carbachol (5 mg). Hematoxylin and eosin staining and immunohistochemistry was performed on frozen sections from the stomach using rabbit anti-gastrin. We found that CaSR deficient mice do not secrete gastrin in response to intraluminal stimulation with calcium, peptone, L-phenylalanine and elevated pH. However, CaSR deficient mice responded to parenteral bombesin and carbacol similar to WT mice. The gastrin response for ad libitum and gavage feeding in the heterozygous and WT littermates was similar to that observed for WT C57/B6 control mice. High Ca++ dietary correction of plasma Ca++ in the CaSR deficient mice did not restore their gastrin response. CaSR deficient mice expressed a decreased number of antral G cells and gastrin content. They also had an elevated resting gastric pH and reduced basal acid secretion, although they displayed a normal gastric acid secretory response to exogenous gastrin and histamine. From these studies we learned that gastric CaSRs are necessary for the physiological sensing of intraluminal nutrients such as rat chow, peptone, Phe and elevated pH that results in the stimulated release of gastrin from antral G cells. Whether the sensing of these stimulants is directly mediated by CaSRs on gastric antral G cells awaits further studies using isolated G cells. In addition, we found an unexpected role of CaSR in determining antral G cell number.